Old female and male rats are heterogeneous in their fever responses to lipopolysaccharide (LPS); some get moderately good fevers, some no fevers, and some become hypothermic. LPS stimulates the immune system to produce proinflammatory cytokines, such as interleukin-1beta (IL-1beta), which induce fever by causing synthesis and release of prostaglandin E2(PGE2). Old rats have very high levels of these cytokines. yet do not get good fevers. We have evidence that if IL-1 beta or PGE2 is infused into the brains of old rats, they show very good fever responses. Therefore, the problem must be in the periphery, but it cannot be in the lack of production of proinflammatory cytokines. We will measure the PGE2 released in the hypothalamus after LPS, which we predict will be lower than that induced in young rats after the same procedure. Old rats also have very high plasma levels of corticosterone (CORT), and CORT inhibits cytokine action and fever. Possibly the overproduction of cytokines in old animals is an attempt by the CNS to overcome the inhibiting effects of excess CORT. If so, then old rats injected with a CORT receptor antagonist should get higher fevers than controls will, and may need to generate lower levels of proinflammatory cytokines. It may also be that old rats do not get as high a fever as do young rats because they are generating higher levels of anti-inflammatory cytokines. One goal of this proposal is to measure brain, tissue, and plasma pro- and anti-inflammatory cytokine and hypothalamic-pituitary- adrenal (HPA) axis product levels in old rats to determine differences in the profiles that might explain differences in responses to LPS. We have recently found that when young rats were injected with LPS and left at an ambient temperature (Ta) of 23 C for three hr, they all developed fevers, as expected. Similarly treated old rats either had blunted fevers, no fever, or became hypothermic, also as anticipated. Unexpectedly, three hr post-injection. when the old rats were placed in a thermal gradient, they chose warm positions and became febrile. Thus, the drive towards fever was present in the old rats but could not be expressed without behavioral choice. We want to understand the basis of this surprising result.